The present invention provides methods for preventing and/or treating hearing loss and loss of the sense of balance. More specifically, the present invention provides methods for preserving sensory hair cells and cochlear neurons in a subject by administering an effective amount of compounds of Formula I and/or Formula II.
The mammalian ear functions by transforming sound waves, or airborne vibrations, into electrical impulses. The brain then recognizes these electrical impulses as sound. The ear has three major parts, the outer, middle, and inner ear. Sound waves enter the outer ear and cause the eardrum to vibrate. The vibrations of the eardrum are transmitted serially through the three ossicles in the middle ear- the malleus, incus and stapes, also called the hammer, anvil and stirrup, respectively. The stirrup transmits the vibrations to the inner ear. The inner ear comprises the cochlea and is connected to the middle ear via the oval and round windows. The inner ear is filled with fluid and vibrations transmitted to the inner ear cause fluid movement in the cochlea of the inner ear. Fluid movement in the cochlea causes movement of sensory hair cells which initiates nerve impulses. These nerve impulses are interpreted in the brain as sound.
The sensory hair cells are contained in the organ of Corti, which coils around the inside of the cochlea. Within the organ of Corti there are inner and outer sensory hair cells. The outer sensory hair cells are present in three rows, designated OHC1, OHC2 and OHC3; inner sensory hair cells are present in one row. The sensory hair cells are attached to the basilar membrane and contact the tectorial membrane. Movement of fluids within the inner ear causes a movement of the basilar membrane relative to the tectorial membrane. This relative movement causes the cilia on the sensory hair cells to bend and leads to electrical activity. Cochlear ganglion neurons below the sensory hair cells transmit this electrical activity to auditory regions of the brain via the auditory nerve.
The fluid filled inner ear, also called the membranous labyrinth, further contains the two mammalian organs of equilibrium which make up the vestibular system. The first organ of equilibrium is composed of the saccule and utricle which detect and convey information on body position relative to gravitational force. Both the saccule and utricle also contain sensory hair cells. Tiny particles of calcium carbonate lie on the sensory hair cells in the saccule and utricle and bend the cilia to stimulate the sensory hair cells to send appropriate signals to the brain, including xe2x80x9cupxe2x80x9d, xe2x80x9cdownxe2x80x9d, xe2x80x9ctiltxe2x80x9d and xe2x80x9caccelerationxe2x80x9d in a particular direction. Sensory hair cells in the utricle detect linear movement in the horizontal plane while sensory hair cells in the saccule detect movement in the vertical plane.
The second organ of equilibrium is composed of three semicircular canals which detect and convey information on movement, detected as fluid acceleration, to the brain. The semicircular canals are also lined with sensory hair cells, and are arranged at near 90 degree angles with respect to one another and can detect movement in three dimensions. As the head is accelerated in one of these planes, fluid movement in the canal corresponding to the plane of movement stimulates movement of the cilia of the sensory hair cells.
The vestibular organsxe2x80x94the saccule, the utricle and the semicircular canals xe2x80x94stimulate nerve endings of vestibular ganglion neurons which then transmit information to a number of sites for different purposes. For example, information is transmitted from the vestibular system to the eyes to keep the eyes focused on a target while the body is moving. Neurons also interconnect the vestibular system and the cerebellum for producing smooth and coordinated bodily movements. Vestibular information also travels down the spinal cord to muscles in order to maintain proper posture and balance.
Significant hearing loss causing communication problems occurs in about ten percent of the population and more than one third of us will have substantial hearing loss by old age. Noise-induced hearing loss is estimated to be the cause of hearing loss in about one-third of the 28 million Americans with hearing loss (NIH Publication No. 97-4233, April 1997). In most cases, the auditory impairment results from the death of sensory hair cells in the organ of Corti. Sensory hair cells are delicate cells and thus are susceptible to damage from several sources, including, but not limited to, noise, infection, drugs, vascular insufficiency and idiopathic effects. Idiopathic effects are those effects which arise spontaneously or from an unknown or obscure cause.
Presbycusis is age-related hearing loss. Four distinct types of presbycusis have been described which are based upon audiograms and pathological analyses: 1) sensoryxe2x80x94loss of sensory hair cells and secondary degeneration of cochlear neuronal structures, 2) neuralxe2x80x94loss of cochlear ganglion cells and/or nerve, 3) metabolicxe2x80x94atrophy of the stria vascularis, and 4) mechanicalxe2x80x94stiffening of the basilar membrane (Schuknecht, Arch. Otol., 80:369-382, 1964). The neural and metabolic causes of presbycusis may also result in the ultimate loss of hair cells.
While no frequency data is associated with the descriptions of the types of presbycusis, sensory presbycusis is the most common (Working Group on Speech Understanding and Aging, Speech understanding and aging, J. Acoust. Soc. Am. 83:859-895, 1988). Johnsson et al. have described both degeneration of the stria vascularis and hair cell loss in 150 patients ranging in age from newborn to 97 years of age. Both are progressive and most pronounced in elderly subjects. An age-related loss of hair cells of the vestibular apparatusxe2x80x94saccule and utriclexe2x80x94was also noted that may account for vestibular disturbances in the elderly (Johnsson et al., Ann. Otol. Rhinol. Laryngol. 81:179-193, 1972; Johnsson et al., Ann. Otol. Rhinol. Laryngol. 81:364-376, 1972).
We are born with a complement of about 16,000 sensory hair cells and 30,000 auditory neurons in each ear. These cells do not regenerate during postnatal life. Therefore, loss of each cell, due to, for example, noise, infection, toxic drugs (such as platinum-based cytotoxic agents and aminoglycosides) or idiopathic effects is irreversible and cumulative. If enough sensory cells are lost, the end result can be total deafness.
Noise trauma is a widespread cause of hearing loss. Sound overexposure has been demonstrated to lead to sensory hair cell apoptosis in the avian inner ear (Nakagawa et al., ORL, 59:303-310, 1997). There is increasing evidence that the death of sensory hair cells caused by drugs such as platinum-based cytotoxic agents and aminoglycosides is partially, if not mainly, apoptotic. Noise-induced sensory hair cell loss in the cochlea apparently has a similar mechanism.
Aminoglycosides are widely used antibiotics used in patients with Gram-negative bacterial infections (Paparella et al, Otolaryngology, 1817, Saunders-Philadelphia, 1980). Aminoglycosides are known to cause damage to sensory hair cells and thereby affect hearing. Aminoglycosides include, but are not limited to, neomycin, kanamycin, amikacin, streptomycin and gentamicin. Amikacin causes apoptosis of sensory hair cells in rat cochleas (Vago et al., NeuroReport 9:431-436, 1998). Gentamicin treatment results in degeneration of sensory hair cells in guinea pigs (Li et al., J. Comparative Neur., 355:405-417, 1995; Lang et al., Hearing Res., 111:177-184, 1997).
The loss of sensory hair cells in the cochlea has been attributed to aminoglycoside ototoxicity. Apoptosis of sensory hair cells of guinea pigs was observed following chronic treatment with aminoglycoside (Nakagawa et al., Eur. Arch. Otor., 254:9-14, 1997; Nakagawa et al., Acta Otol., 255(3):127-131, 1998). Studies have assessed the protective effect of various polypeptides on sensory hair cells in the cochlea. (See, for example, Malgrange et al., Abstr. Assoc. Res. Otol., 17:138, 1994; Low et al., J. Cell. Physiol. 167:443-450, 1996; and Ernfors et al., Nature Medicine, 2:463-467, 1996). Ernfors et al. noted that, although the peptide NT-3 is a potent factor for preventing the degeneration of spiral ganglion neurons, NT-3 xe2x80x9cinsufficiently protects the hair cellsxe2x80x9d (Ernfors et al., Nature Medicine, 2:463-467, 1996).
Platinum-based cytotoxic agents include, but are not limited to, cisplatin and carboplatin. Cisplatin is a widely used antitumor drug which causes structural changes in the inner ear and peripheral sensory neuropathy. Hearing loss due to cisplatin is usually permanent and cumulative.
Rapid onset hearing loss, also named sudden sensorineural hearing loss, may also occur without any obvious reasons. Hearing loss in these situations develops either instantaneously or after a few hours. The location of the damage is within the cochlea, and has been partially attributed to sensory hair cell damage. Such hearing loss may be due to idiopathic causes or as a result of other causes, including vascular disease, hypertension and thyroid disease and viral infection by viruses including mumps, measles, mononucleosis, adenovirus, (Thurmond et al., J. La. State Med. Soc., 150:201-203, 1998).
Damage to sensory hair cells and cochlear neurons may also occur as a result of infection. For example, the onset of meningitis has been linked to hearing loss as a result of damage to sensory hair cells. (Blank et al., Arch. Otol. Head Neck Surg., 120:1342-1346, 1994). Meningitis as a result of E. Coli infection also damages sensory hair cells (Marwick et al., Acta Otol. (Stockholm), 116(3):401-407, 1996). Toxins from Streptococcus pneumoniae have also been linked to damage to sensory hair cells (Comis et al., Acta Otol. (Stockholm) 113(2):152-159, 1993).
Accessory epithelial structures of the cochlea and innervating cochlear neurons stay intact for a considerable length of time following trauma, but undergo secondary retrograde degeneration following the loss of IHCs (Ylikoski et al., 1974; Hawkins, 1976).
Several authors have recently shown that the cochlear sensory hair cells can be protected to some extent from both ototoxic and noise damage using various compounds. This was shown in animal model systems using hair cell counts and hearing threshold measurements, e.g. by auditory brainstem responses. The most commonly used therapeutic compounds have been antioxidants or free radical scavengers.
In addition to immediate mechanical damage, oxidative stress associated with the formation of free radicals (see discussion) and excitotoxicity (Basile et al., Nature Med. 2:1338-1343, 1996) have been implicated in the pathogenesis of hearing loss. Evidence in various cell lines and in vivo neuronal and non-neuronal model systems shows that apoptotic death can be induced by both oxidative stress and excitotoxicity (reviewed by Pettmann and Henderson, Neuron 20:633-647, 1998). In the inner ear, necrotic hair cell death, characterized by cellular swelling, has been demonstrated following acoustic trauma (Kellerhals, Adv. Oto-Rhino. Laryng. 18:91-168, 1972). More recent data, obtained in the ototoxic drug-damaged inner ear, have suggested that hair cells may also die through apoptosis, based on the observations of nuclear fragmentation (Forge, Hear. Res. 19:171-182, 1985; Lee et al. J. Comp. Neur., vol.355, 405-417, 1995;
Liu et al., Neuroreport 9:2609-2614, 1998; Nakagawa et al., Eur. Arch.
Otorhinolaryngol. 255:127-131, 1998; Vago et al., NeuroReport 9:431-436, 1998). However, the contribution of apoptotic hair cell death to the loss of hearing function is not known. In addition, the molecular mechanisms involved in commitment to hair cell death are unknown.
Antioxidants and free radical scavengers have been tested because both ototoxic drug and noise damage have been postulated to produce an excess of reactive oxygen species (ROS) in the inner ear. Overproduction of ROS is thought to cause sensory hair cell damage by overwhelming the cochlea""s antioxidant defense system (Ravi et al., Pharmacology and Toxicology 76:386-394, 1995).
One of the signaling cascades that has been shown to mediate apoptotic death in response to a variety of stressful stimuli is the c-Jun-N-terminal kinase (JNK) pathway, also known as the stress-activated protein kinase (SAPK) pathway (Dxc3xa9rijard et al., Cell 76:1025-1037, 1994; Kyriakis et al., Nature 369:156-160,1994). JNK activation by phosphorylation has been shown to be important for neuronal cell death after trophic factor withdrawal in vitro and after injury in vivo (Xia et al., Science 270:1326-1331, 1995; Dickens et al., Science 277:693-696, 1997; Yang et al., Nature 389:865-870, 1997). JNKs in turn phosphorylate c-Jun, a component of the transcription factor AP-1. Blockade of c-Jun activation and transcriptional activity in vitro has been shown to prevent neuronal cell death (Estus et al., J. Cell Biol. 127:1717-1727, 1994; Ham et al., Neuron 14:927-939, 1995; Watson et al., J. Neurosci. 15:751-762, 1998). Recent data from c-Jun phosphorylation-deficient mice (Behrens et al., Nature Gen. 21:326-329, 1999) and from JNK knock-out mice (Yang et al., 1997) show that c-Jun phosphorylation is essential for injury-induced neuronal death.
Neurotrophic factors including NT-3, BDNF and GDNF have also been shown to be important for protection of neurons within the inner ear, and may also have a role in hair cell protection after cochlear insult (Gabaizadeh et al., Acta Otol. (Stockholm), 117:232-235, 1997; Ernfors et al. Ototoxicity: Basic Research and clinical applications, Savelletri di Fasano, Italy, Jun. 18-20, 1998, Abstract No. 12; Keithley et al., Neuroreport, 9:(10), 2183-2187, 1988; Shoji et al., ARO Meeting, St. Petersburg Beach, Fla., Abstract No.539, 1998; Tay et al., ARO Meeting, St. Petersburg Beach, Fla., Abstract No.538, 1998; Ylikoski et al., Hear Res 124:17-26, 1998). The loss of mechanoreception following cisplatin-induced neuropathy has been reversed through the administration of NT-3 (Gao et al., Ann. Neurol., 38:30-37, 1995).
Table 1, below, summarizes some compounds tested for protection of cochlear sensory hair cells from damage, in vivo.
One problem in drug-based therapy of cochlear lesions is the limited biological activity of exogenously administered polypeptides. The biological half-life of many neurotrophic factors has been shown to be very short. On the other hand, degeneration of sensory hair cells does not occur instantly; a large number of sensory hair cells at first seem to be reversibly damaged and might recover if treated promptly. After noise exposure, the typical pattern of cellular damage in the organ of Corti takes 2-3 weeks to be complete. Affected cochlear neurons start to degenerate after noise has destroyed the sensory hair cells and the nerve terminals, 3-4 weeks postexposure.
There is no effective medical treatment to date for auditory sensory hair cell loss. Also, prevention of sensory hair cell degeneration is obscured by the fact that exact molecular mechanisms of damage to the auditory organ are unknown. Consequently, no effective regimen has been developed to prevent or treat damage to sensory hair cells. Therefore, there exists a need for compositions and methods to prevent and/or treat sensory hair cell damage.
There is also no effective medical treatment known to date for loss of cochlear neurons. Therefore, a need exists for compositions and methods to prevent and/or treat damage or loss of cochlear neurons.
As is clear from the foregoing discussion, damage to sensory hair cells or cochlear neurons can also affect the vestibular system and can result, for example, in vertigo. Benign paroxysmal positional vertigo (BPPV) affects about 40 to 60 people per 100,000 population every year. Also, Meniere""s disease affects about 40 people per 100,000 population each year. During the course of these and other diseases, the sensory hair cells of the vestibular system have a tendency to degenerate. No effective regimen to date has been developed to prevent or treat damage to sensory hair cells in the vestibular system. Therefore, there exists a need for compositions and methods to prevent and/or treat damage to sensory hair cells and neurons in the vestibular system.
According to one aspect of the invention, a method is provided for preventing hearing loss in a subject comprising administering to said subject an effective amount of a fused pyrrolocarbazole of Formula I having the formula: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
ring D is selected from phenyl and cyclohexene with double bond a-b;
ring B and ring F are independently selected from:
(a) a 6-membered carbocyclic ring in which from 1 to 3 carbon atoms may be replaced by heteroatoms;
(b) a 5-membered carbocyclic ring; and
(c) a 5-membered carbocyclic ring in which either:
(1) one carbon atom is replaced with an oxygen, nitrogen, or sulfur atom;
(2) two carbon atoms are replaced with a sulfur and a nitrogen atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or
(3) three carbon atoms are replaced with three nitrogen atoms, one oxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;
G-X-W is selected from:
(a) (Z1Z2)Cxe2x80x94N(R1)xe2x80x94C(Z1Z2);
(b) CH(R1)xe2x80x94C(=O)xe2x80x94N(R1); and
(c) N(R1)xe2x80x94C(=O)xe2x80x94CH(R1);
Z1 and Z2, at each occurrence, are independently selected from H, H; H, OR; H, SR; H, N(R)2; and a group wherein Z1and Z2 together form a moiety selected from =O, =S, and =NR; with the proviso that at least one of the pairs Z1 and Z2 forms =O;
R is independently selected from H, optionally substituted alkyl, OH, alkoxy, OC(=O)R1a, OC(=O)NR1cR1d, O(CH2)pNR1cR1d, O(CH2)pOR1b, optionally substituted arylalkyl and optionally substituted heteroarylalkyl;
R1 is independently selected from:
(a) H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;
(b) C(=O)R1a;
(c) OR1b;
(d) C(=O)NHR1b, NR1cR1d, (CH2)pNR1cR1d, (CH2)pOR1b, O(CH2)pOR1b and O(CH2)pNR1cR1d,
R1a is independently selected from optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl;
R1b is independently selected from H and optionally substituted alkyl;
R1c and R1d are each independently selected from H, optionally substituted alkyl and a linking group of the formula (CH2)2xe2x80x94X1xe2x80x94(CH2)2;
X1 is independently selected from O, S and CH2;
Q is selected from NR2, 0, S, NR22, CHR23, X4CH(R23), CH(R23)X4, wherein X4 is selected from O, S, CH2, NR22 and NR2; 
R2 is selected from H, SO2R2a, CO2R2a, C(=O)R2a, C(=O)NR2cR2d, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, wherein said optional substituents are one to about three R5 groups;
R2a is independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, OR2b, CONH2, NR2cR2d, (CH2)pNR2cR2d and O(CH2)pNR2cR2d;
R2b is selected from H and optionally substituted alkyl;
R2c and R2d are each independently selected from H and optionally substituted alkyl, or together form a linking group of the formula (CH2)2xe2x80x94X1xe2x80x94(CH2)2;
R3 and R4 are each independently selected from:
(a) H, aryl, heteroaryl, F, Cl, Br, I, CN, CF3, NO2, OH, OR9, O(CH2)pNR11R12, OC(=O)R9, OC(=O)NR11R12, O(CH2)pOR10, CH2OR10, NR11R12, NR10S(=O)2R9 and NR10C(=O)R9;
(b) CH2OR14;
(c) NR10C(=O)NR11R12, CO2R10, C(=O)R9, C(=O)NR11R12, CH=NOR10, CH=NR10, (CH2)pNR11R12, (CH2)pNHR14 and CH=NNR11R12;
(d) S(O)yR9, (CH2)pS(O)yR9 and CH2S(O)yR14;
(e) optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, wherein said optional substituents are one to about three R5 groups;
R9 is selected from alkyl, (CH2)raryl and (CH2)rheteroaryl;
R10 is selected from H, alkyl, (CH2)raryl and (CH2)rheteroaryl;
R11 and R12 are independently selected from H and optionally substituted alkyl, or together form a linking group of the formula (CH2)2xe2x80x94X1xe2x80x94(CH2)2;
R5 is selected from aryl, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxyalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, CN, NO2, OH, OR9, X2(CH2)pNR11R12, X2(CH2)pC(=O)NR11R12, X2(CH2)pOC(=O)NR11R12, X2(CH2)pCO2R9, X2(CH2)pS(O)yR9, X2(CH2)pNR10C(=O)NR11R12, OC(=O)R9, OC(=O)NHR10, O-tetrahydropyranyl, NR11R12, NR10C(=O)R9, NR10CO2R9, NR10C(=O)NR11R12, NHC(=NH)NH2, NR10S(O)2R9, S(O)yR9, CO2R10, C(=O)NR11R12, C(=O)R9, CH2OR10, CH=NNR11R12, CH=NOR10, CH=NR9, CH=NNHCH(N=NH)NH2, S(=O)2NR11R12, P(=O)(OR10)2, OR14, and a monosaccharide wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl, alkylcarbonyloxy, or alkoxy;
X2 is O, S, or NR10;
Y is selected from:
(a) a direct bond;
(b) optionally substituted CH2, CH2CH2 or CH2CH2CH2, wherein said optional substituents are one to about three R19 groups; and
(c) CH=CH, CH(OH)xe2x80x94CH(OH), O, S, S(=O), S(=O)2, C(R18)2, C=C(R19)2, C(=O), C(=NOR20), C(OR20)R20, C(=O)CH(R18), CH(R18)C(=O), C(=NOR20)CH(R18), CHR21C(=NOR20), C(=O)N(R21), N(R21)C(=O), CH2Z, ZCH2 and CH2ZCH2, where Z is selected from C(R20)2, O, S, CO2R20, C(=NOR20) and N(R20);
R18 is independently selected from H, SO2R18a, CO2R18a, C(=O)R18a, C(=O)NR18cR18d, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
R18a is independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted carbocyclyl and optionally substituted heterocyclyl;
R18c and R18d are each independently selected from H and optionally substituted alkyl, or together form a linking group of the formula (CH2)2xe2x80x94X1xe2x80x94(CH2)2;
R19 is independently selected from R20, thioalkyl, halogen, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;
R20 is independently selected from H, alkyl, OH, alkoxy, OC(=O)R18a, OC(=O)NR18cR18d, OC(=S)NR18cR18d, O(CH2)pNR18cR18d, O(CH2)pOR21, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl and optionally substituted carbocyclyl;
R21 is independently selected from H and alkyl;
Qxe2x80x2 is selected from:
(a) a direct bond;
(b) NR6; 
(c) optionally substituted CH2, CH2CH2 or CH2CH2CH2;
(d) CR22R24; and
(e) CH=CH, CH(OH)CH(OH), O, S, S(=O), S(=O)2, C(=O), C(=NOR11), C(OR11)(R12), C(=O)CH(R13), CH(R13)C(=O), C(R10)2, C(=NOR11)CH(R13), CH(R13)C(=NOR11), CH2Zxe2x80x2, Zxe2x80x2xe2x80x94CH2 and CH2Zxe2x80x2CH2;
Zxe2x80x2 is selected from C(R11)(OR12), O, S, C(=O), C(=NOR11) and NR11;
R6 is selected from H, SO2R2a, CO2R2c C(=O)R2a, C(=O)NR1cR1d , optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, wherein said optional substituents are one to about three R5 groups; or
alternatively, when Q is NR2 and Qxe2x80x2 is NR6 or C(R10)2, R2 and R6 or one of R10 are joined together to form: 
wherein R7 and R8 are each independently selected from H, OH, alkyl, alkoxy, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, (CH2)pOR10, (CH2)pOC(=O)NR11R12 and (CH2)pNR11R12; or R7 and R8 together form a linking group of the formula CH2xe2x80x94X3xe2x80x94CH2;
X3 is a bond, O, S, or NR10;
J is selected from a bond, O, CH=CH, S, C(=O), CH(OR10), N(OR10), N(OR10), CH(NR11R12), C(=O)N(R17), N(R17)C(=O), N(S(O)yR9), N(S(O)yNR11R12), N(C(=O)R17), C(R15R16), N+(Oxe2x88x92)(R10), CH(OH)CH(OH) and CH(O(C=O)R9)CH(OC(=O)R9);
Jxe2x80x2 is selected from O, S, N(R10), N+(Oxe2x88x92)(R10), N(OR10) and CH2;
R13 is selected from alkyl, aryl and arylalkyl;
R14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
R15 and R16 are independently selected from H, OH, C(=O)R10, O(C=O)R9, alkyl-OH, alkoxy and CO2R10;
R17 is selected from H, alkyl, aryl and heteroaryl;
R22is 
X5 and X6 are independently selected from O, N, S, CHR26, C(OH)R26, C(=O) and CH2=C;
X7 and X8 are independently selected from a bond, O, N, S, CHR26, C(OH)R26, C(=O) and CH2=C;
X9 and X10 are independently selected from a bond, O, N, S, C(=O) and CHR26;
X11 is a bond or alkylene optionally substituted with NR11R12 or OR30;
R23 is selected from H, OR27, SR27, R22 and R28;
R24 is selected from R, thioalkyl, and halogen;
R25 is selected from R1 and OC(=O)NR1cR1d;
R26 is selected from H, optionally substituted alkyl and optionally substituted alkoxy, wherein
(1) ring G contains 0 to about 3 ring heteroatoms;
(2) any two adjacent hydroxyl groups of ring G can be joined to form a dioxolane ring;
(3) any two adjacent ring carbon atoms of ring G can be joined to form a fused aryl or heteroaryl ring; with the provisos that:
(a) when X11 is a bond, ring G can be heteroaryl; and
(b) ring G:
(i) contains at least one carbon atom that is saturated;
(ii) does not contain two adjacent ring O atoms;
(iii) contains a maximum of two C(=O) groups;
R27 is selected from H and alkyl;
R28 is selected from aryl, arylalkyl, SO2R29, CO2R29, C(=O)R29, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;
R29 is selected from alkyl, aryl and heteroaryl;
R30 is selected from H, alkyl, acyl and C(=O)NR11R12;
m is independently selected from 0, 1, and 2;
p is independently selected from 1, 2, 3, and 4;
r is independently selected from 0, 1, and 2;
y is independently selected from 0, 1 and 2; and
z is selected from 0, 1, 2, 3 and 4;
with the provisos that at least one of Y and Qxe2x80x2 is a direct bond, when Y is a direct bond, Qxe2x80x2 is other than a direct bond, when Qxe2x80x2 is a direct bond, Y is other than a direct bond, and when rings B and F are phenyl, G-X-W is CH2NHC(=O), Y is a direct bond, Q is NR2 and Qxe2x80x2 is NR6 where R6 is joined with R2 to form 
then R3 is other than CH2SCH2CH3.
Another aspect of the invention provides a method for preventing loss of sense of balance in a subject comprising administering to said subject an effective amount of a fused pyrrolocarbazole of Formula I, as defined above.
Yet another aspect of the invention provides a method for preventing the death of sensory hair cells in a subject comprising administering an effective amount of the compound of Formula I, as defined above.
A further aspect of the invention provides a method for preventing sudden sensorineural hearing loss due to the loss of sensory hair cells comprising administering an effective amount of the compound of Formula I, as defined above.
Another aspect of the invention provides a method for preserving function of sensory hair cells prior to or subsequent to trauma in a subject comprising administering an effective amount of the compound of Formula I, as defined above.
Yet another aspect of the invention provides a method for treating damaged sensory hair cells comprising administering an effective amount of the compound of Formula I, as defined above.
A further aspect of the invention provides a method for preventing death of cochlear neurons in a subject comprising administering an effective amount of Formula I, as defined above.
A further aspect of the present invention provides a method for preventing hearing loss in a subject comprising administering to said subject an effective amount of the compound of Formula II; 
A further aspect of the present invention provides a method for preventing loss of sense of balance in a subject comprising administering to said subject an effective amount of the compound of Formula II as defined above.
A still further aspect of the present invention provides a method for preventing death of sensory hair cells in a subject comprising administering to said subject an effective amount of the compound of Formula II as defined above.
A further aspect of the present invention provides a method for preventing sudden sensorineural hearing loss in a subject due to death of sensory hair cells comprising administering to said subject an effective amount of the compound of Formula II as defined above.
A further aspect of the present invention provides a method for preserving function of sensory hair cells prior to or subsequent to trauma in a subject comprising administering to said subject an effective amount of the compound of Formula II as defined above.
A still further aspect of the present invention provides a method for preventing death of cochlear neurons in a subject comprising administering to said subject an effective amount of the compound of Formula II as defined above.